This Program Project (PP) application represents a comprehensive collaborative effort to obtain information on the endocannabinoid sites of action that will ultimately be used to develop novel therapeutic drug analogs. The proposal work will seek to explore the pharmacophoric requirements for activation/deactivation/desensitization of the CB1 and CB2 cannabinoid receptors. It also includes efforts to successfully image the CB1 binding sites. During the current funding period, we have made very substantial progress in the above goals and also developed novel approaches which are now being integrated in our current submission. The goals of this competing renewal are further refined and extended to address important developments in the field, some of which were generated under the auspices of this PP. This PP will seek.to obtain detailed knowledge on the structure, function and distribution of the CB1 and CB2 cannabinoid receptors. The information will serve as a basis for the design of new drug molecules with selectivity for these two receptors. The work will be accomplished through an integrated interdisciplinary effort centered around the development of high affinity ligands from the different classes of CBics and includes: (a) obtaining information on the CB1 and CB2 binding sites using covalent and non-covalent ligands. The pharmacophoric requirements for the two receptors will be compared to those of the endocannabinoid deactivating enzymes (FAAH, MGL and COX2) and the transporter system (ANT); (b) the in vivo imaging of CB1 receptors, in mammalian brains using PET and SPECT (future work will seek to in vivo image other cannabinergic targets in the brain using methods developed here); (c) defining the pharmacophoric features of a ligand associated with CB1 and CB2 activation and desensitization and developing selective ligands for each of the two processes. The role of CBR dimerization will also be explored. The PP will involve an intense joint effort between collaborating laboratories committed to utilize common resources and share information in order to accomplish common goals in an efficient, effective and highly synergistic manner. The information from the proposed work will be used to develop novel therapies for combating drug addiction and developing non-addictive medications for the management of pain and nausea. These may prove to be important for combating the scourge of addiction and should be contributions of great value to public health.